A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma

Carcinogenesis. 2013 Jul;34(7):1529-35. doi: 10.1093/carcin/bgt092. Epub 2013 Mar 13.

Abstract

Interleukin (IL)-32 is an intracellular proinflammatory mediator that strongly modulates the inflammatory reaction. Recent studies have suggested the involvement of IL-32 in the pathogenesis of malignancies. We aimed to assess whether a known germ-line polymorphism in the IL32 promoter modulates IL-32 expression, and whether it influences susceptibility and/or outcome of epithelial cell-derived thyroid carcinoma (TC). In this study, IL32 genotype was assessed in 139 TC patients and 138 healthy controls and was correlated with TC susceptibility and clinical outcome. Furthermore, IL-32 messenger RNA expression and protein were assessed in TC tissues and functional consequences of genetic variants of IL32 were studied in a model of human primary immune cells. Results demonstrate substantial IL-32 expression in TC tumor tissue. Lipopolysaccharide (LPS) stimulation of primary immune cells revealed 2-fold higher expression of IL-32γ, but not IL-32β, in cells homozygous for the ancient T allele. Furthermore, production of LPS-induced cytokines was increased in cells bearing this T allele. Genetic analysis revealed that the ancient T allele was overrepresented in TC patients with odds ratio (95% confidence interval) = 1.71 (1.06-2.75). In addition, the cumulative radioactive iodine (RAI) dose received after total thyroidectomy was significantly higher in TC patients bearing the ancient T allele. In conclusion, individuals bearing genetic variants of IL32 that lead to an increased IL-32γ gene expression and higher production of proinflammatory cytokines have higher risk for developing epithelial cell-derived TC. Subsequently, they require higher dosages of RAI to achieve successful tumor remission. These data suggest an important role of IL-32 in the pathogenesis of TC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Case-Control Studies
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • Interleukins / genetics*
  • Interleukins / metabolism
  • Iodine Radioisotopes / administration & dosage
  • Iodine Radioisotopes / therapeutic use
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Male
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic*
  • Risk Factors
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • Thyroidectomy

Substances

  • IL32 protein, human
  • Interleukins
  • Iodine Radioisotopes
  • Lipopolysaccharides